Development of Anti-Cancer Therapeutics that Modulate the RAD51-BRCA2 Complex
Abstract
Rd51 is important for repairing double-strand breaks in DNA by recombinational repair, a pathway that utilizes a homologous template usually provided by the sister chromatid for somatic cells. This function may be essential since mammalian cells deleted for Rad51 exhibit chromosomal instability, are unable to sustain proliferation and senesce or die. In order to function, Rad51 associates with Brca2, a protein important for suppression of breast cancer. Rad51 associates with Brca2 in two domains: the most amino- terminal domain is mediated by the BRC motifs (encoded in exon 11) and in the most COOH- terminal domain by a single region (encoded by exon 27). COOH terminal deletions that remove some but no all of these regions increase replicative senescence and sensitivity to ionizing radiation and cross-linking agents, suggesting that the Rad51 - Brca2 association is biologically important. Here we describe a peptide, derived for the Rad51 interacting region encoded in exon 27 that biochemically interacts with a Rad51 filament that is associated with DNA. Additionally, exposure to the peptide causes a reduction of replication, disruption of Rad51 foci and programmed cell death. We propose that the peptide forms a nonproductive association with Rad51 that inhibits Rad51 function. Such a peptide may serve useful as an anti-cancer agent.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2004
- Accession Number
- ADA427067
Entities
People
- Edward P. Hasty
Organizations
- University of Texas Health Science Center at San Antonio